This proposal describes a five-year training program for an academic career as a physician scientist. The principal investigator completed medical school, residency, and fellowship as well as a neurosciences Ph.D. program. He will begin the transition to independent investigator by pursuing a five-year mentored research program that is an extension of his graduate school thesis project. The goal of the proposed investigation is to more clearly define the roles of cardiac beta2ARs in vivo. Preliminary studies performed by the principal investigator suggest that during short-term continuous periods (14 days) of beta1AR stimulation, beta2AR activation reduces mortality, diminishes myocyte apoptosis, and prevents right heart dysfunction. The proposed project will expand upon these findings. The specific aims: 1a) to investigate whether the protective effects of beta2AR activation are mediated by cardiac or non-cardiac beta2ARs using conventional beta2KO and conditional cardiac-specific beta2KO mice. 1b) to investigate whether altering beta2AR signaling by disrupting the beta2AR PDZ motif diminishes the protective effects of beta2AR activation in vivo; 2) to determine whether long-term (months of) continuous beta1AR activation leads to functional impairment of the heart, and to investigate whether beta2AR stimulation protects the heart during long-term continuous beta1AR activation; 3) to investigate whether reductions in myocyte apoptosis during betaa2AR activation are chamber specific or uniform throughout the myocardium. To determine whether altering beta2AR signaling by disrupting the beta2AR PDZ motif diminishes beta2AR-mediated reduction in myocyte apoptosis. To investigate changes in gene and protein expression during periods of continuous beta1AR activation. The project mentor, is a recognized expert in the field of adrenergic receptor biology. He is a Professor of Molecular and Cellular Physiology and Medicine and has trained numerous postdoctoral fellows and graduate students. An advisory committee that includes a molecular pharmacologist, a cardiologist, and another adrenergic receptor biologist will enhance the principal investigator's resources.